Pharmacogenomics can play an important role in identifying responders and non-responders to medications, avoiding adverse events, and optimizing drug dose.’ — FDA
PGx — the shorter and easier-to-spell abbreviation for pharmacogenomics — can be considered an “easy button” for providers to understand why certain drugs work well for some patients and not for others.
As we’ve noted in other blogs, many physicians remain skeptical of PGx’s value in clinical practice, and we know that scientific evidence is still emerging for many drug-gene combinations. While there are already many applications of PGx in cancer, pain and psychiatry, we’d recommend getting started with common drugs used in highly prevalent diseases.
A reminder that the concept and value of PGx aren’t new. While there’s been a considerable growth in interest in genetic influences of drug response over the past decade-plus, it actually stems back more than 50 years. In 1957, shortly after the discovery of a genetic predisposition toward primaquine-induced toxicity, scientists proposed that inheritance might underlie much of the disparity among individuals in drug response. The term pharmacogenetics was introduced two years later. With the advent of the Human Genome Project in 1990 came a resurgence of interest in determining genetic contributions to drug response. The mapping of the human DNA gene-containing sequence was completed with 99% accuracy in 2003, two years earlier than planned.
Since then, continued advances in personal genome sequencing are revealing each individual’s complete heritable genetic identity —a patient’s “blueprint” of genetic material — as well as his or her likely response to various medications based on the person’s liver enzymes and activities.
Delivering personalized care by knowing patients down to their genes
So what, simply stated, is pharmacogenomics? PharmGKB describes it as the study of the relationship between an individual’s genetic variations and how that person’s body metabolizes medications. According to a leading pharmacotherapy textbook, PGx’s goal is “to optimize drug therapy and limit drug toxicity based on an individual’s genetic profile.” These descriptions well-articulate a complex process that can have a dramatic impact on shortening the “hit-or-miss” nature of the medication prescribing therapeutic odyssey. This way, you can more effectively deliver personalized care that has maximum safety and effectiveness, especially under the growing number of value-based care plans.
Throughout this and other blogs, we’ll provide helpful citations from respected sources such as the Clinical Pharmacogenetics Implementation Consortium. An international consortium, CPIC was formed in 2009 to address the barriers of implementing PGx testing in a clinical setting because of the difficulty in translating these complex genetic laboratory test results into actionable prescribing decisions.
CPIC creates, curates and posts free peer-reviewed, evidence-based, updatable and detailed drug-gene clinical practice guidelines. These guidelines use an evidence-ranking system by gene, drug, guideline, level of evidence to date, and FDA label instructions for PGx testing effectiveness of drug-gene combinations. It’s considered the most clinically validated or “gold standard” in PGx because it has the strongest research and documentation for each of its recommendations.
How a patient metabolizes drugs
To date, the CPIC drug-gene pairs table includes a total of 355 drug-gene interactions (DPIs), representing 223 unique drugs and 127 unique genes identified as impacting drug metabolism. Others have been tested but no impact has been discovered, while many others have yet to be researched due to the cost, typically borne by drug manufacturers. Though the body of evidence continues to expand, today there are 25 to 30 interactions that have been broadly accepted where PGx testing is recommended or required to supply providers with actionable information to support their decision-making.
As you learn more about applying PGx, a helpful resource is the Flockhart Table, separating medications by their class (NSAIDs, beta blockers, etc.) and enabling you to drill down to references to literature regarding substrates of liver enzymes that metabolize the meds. It also notes what are strong, moderate or weak inhibitors and inducers that compete with other drugs for a particular enzyme; this affects the optimal level of metabolism of the substrate drug that can often affect an individual’s response to that medication…typically making it less or completely ineffective.
Why phenotypes matter
People present as one of four phenotypes:
- Ultra-rapid. Action required! If a medication is a prodrug — an inactive derivative of a drug that turns into the active drug once metabolized by the body — a person who is an ultra-rapid metabolizer could receive too much medication too quickly, potentially causing safety issues. For instance, someone sensitive to codeine could metabolize more of the medication into morphine, receiving an exponentially larger dose of it; this could lead to an overdose and severe side effects. Conversely, a non-prodrug could be metabolized too fast and not remain in the body long enough to have the desired clinical benefits. In either case, knowing that a patient is an ultra-rapid metabolizer can be critical as a medication and its dosage are considered.
- Extensive. No action required. This is considered a typical or “normal” response as described in the clinical literature for this drug. PGx data is unlikely to affect a prescribing decision.
- Intermediate. Intervention considered. This is really the “sweet spot” where a clinical pharmacist armed with PGx data and advanced training in interpreting it really adds value. Here, the pharmacist should consult with the prescribing physician and the patient to consider a change based on the PGx data for that individual. They can discuss the multivariable genotypes that come into play in determining how a patient falls into this “grey area” of a person presenting as an intermediate phenotype.
- Poor. Action required! While poor metabolizers are the opposite of ultra-rapid, the action should be the same; action is required because they metabolize medications slowly, if at all. If a medication is a prodrug, these patients won’t obtain therapeutic doses of the drug, leading to therapeutic failure. Otherwise, poor metabolizers have decreased rates of drug clearance, putting them at an increased risk of super-therapeutic doses, significantly increasing the risk of side effects and adverse drug reactions.
Delivering key takeaways you can USE
Multiphasic genotypes. Phenotypes. Enzymes. Metabolism status. Common inhibitors and inducers. Evidence-based recommendations for interventions. There’s a lot to be understood when integrating pharmacogenomic information into the decision-making process for each patient. But there’s also a huge amount of value in making PGx an integral part of personalized, value-based care.
Those of us who have dedicated a significant portion of our education and careers to it are here and anxious to help. Keep reading our posts as we work to distill this complex subject down to key takeaways you can use every day in your practice to deliver truly exceptional care in the new millennium.
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Co-written by Bob Kropp, MD, MBA, CPHI, a double-board-certified physician and Johns Hopkins-trained informaticist with 12 years of clinical practice and 20 years of managed care experience who consults with RxLive.
To learn more about RxLive pharmacogenomic testing and medication counseling services, contact us at kristen@rxlive.com.
You may also want to check out the following:
Saving $$S Through Pharmacogenomics
How Pharmacists And Pharmacogenomics Can Shorten Your Medication Prescribing ‘Odyssey’ And Improve Your Patients’ Health
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